Certain 1-dialkyl amino methyl, 3-alkyl pyrazoles



2,928,842 CERTAIN l-DIALKYL AMINO METHYL, 3-ALKYL PYRAZOLES George Karmas, Somerville, N..l., assignor to Ortho This invention relates to Mannich bases of 3-substituted pyrazoles. These novel compounds possess particular value as anti-convulsants and are useful in the treatment of epilepsy.

Epilepsy has been defined as a cerebral dysrhythmia which may or may not be accompanied by loss of consciousness and body movements. It is now known that epileptic convulsions are related to the flow of electricity from neurons of the cerebral cortex. The type of chemical reaction which is responsible for these cerebral neuronal discharges is not known, but generally, convulsions and loss of consciousness are characterized by abnormally fast brain waves. When the patient suffers loss of consciousness and convulsions, the seizures are referred to as grand mal, a form of major epilepsy. However, convulsions do not necessarily accompany epilepsy, and in some instances consciousness is not lost. When the patient loses consciousness but convulsions are not observed, the attacks are known as petit mal. A third type of epilepsy has been clinically classified as psychomotor epilepsy.

Many-drugs areknown which reduce or diminish epileptic seizures in man. In general, those drugs which will act as depressants of nervous transmission are effective for this purpose. The hypnotics, such as the barbiturates, are effective in doses suificient to produce anesthesia. Phenobarbital is one of the better anticonvulsants, but must be administered in hypnotic doses. The related hydantoins and oxazolidinediones have also been found to possess anti-convulsant properties. Such drugs, however, interfere to a greater or lesser extent with the normal activities of the patient.

It is most important, that any drug which is used as an anti-convulsant have very low toxicity since the nature of epilepsy requires that the patient use the drug daily and over a long period of time. The ideal anti-convulsant drug should be non-toxic, well tolerated, long acting, and devoid of sedative effects.

It is a purpose of this invention to provide a method of reducing or eliminating convulsions in animals and in man by administering anti-convulsant compositions. Our new compositions are useful for veterinary purposes. Effectiveness has been found for a variety of animals, including dogs, mice, rats, and monkeys.

It is a further object of this invention to provide an anti-convulsant composition in-unit dosage form which has a high protective index and is non-toxic in use over a long period of time.

Still another object of this invention is to provide Mannich bases of 3-substituted pyrazole compositions for use in the treatment of epilepsy.

The present invention is particularly concerned with the Mannich bases of 3-alkylpyrazoles having the structure . R1 I N s in which R is an alkyl' radical of from 9 to 11 carbon atoms and R and R are alkyl radicals the total number of carbon atoms in both R and R being from 2 to 4. it has been found that the aforesaid pyrazoles have unexpected and unobvious properties of great value in com bating epilepsy. These compositions may take the form of tablets, powders, capsules, or other dosage forms which will be particularly useful for oral ingestion. The compositions may take the form of active materials, namely the Mannich bases of 3-substituted pyrazoles, ad-

mixed with solid diluents and/ or tableting adjuvants such as corn starch, sucrose, lactose, magnesium stearate, talc, aluminum hydroxide, calcium carbonate gums such as acacia, or the like. Any of the tableting materials used in pharmaceutical practice may be employed where there is no incompatibility with the Mannich base. The material may be placed in a gelatin capsule and administered in that form. Alternatively, the Mannich base may be emulsified in a liquid in which it is not soluble.

It has been found that only certain Mannich bases of the 3-substituted pyrazole series are effective in combating epilepsy. Insofar as is known, the physiological properties of the Mannich bases of 3-substituted pyrazoles have not been heretofore investigated; nor have any of these compounds beenused for therapeutic purposes..

Anti-convulsant drugs may be assayed in the laboratory by the minimum electro-shock method. In this procedure, the drug is administered orally to the animals under test. After one hour, the animal is subjected to a direct-- current stimulus that is approximately equal to three times the current necessary to produce maximum seizures.

The effectiveness of various Mannich bases as anti-convulsants is summarized in Table I. In this table, the first column gives the effective dose in milligrams per kilogram required to prevent convulsions in one-half of the animals subjected to the minimum electro-shock procedure. The second column indicates the amount of drug in milligrams per kilogram that produced neurological toxic symptoms in one-half of the experimental group. The third column of this table reports the amount of drug, again in milligrams per kilogram, that was fatal to fifty percent of the test group. Column four indicates the protective index (N.T. +ED and the fifth column gives the therapeutic index (LD +ED TABLE I E176 NIS LD T.I. P.I

l-diethylaminomethyl-S-nonylpyrazule 125200 500 900 4.5-7.0 l-dicthylaminomethyl-3-dccylpyrazole 75 250 500 6.7 2.0

l-diethrlaminomethyl-3 mdeevlpvraz-le... 104 325 900 8.0 2.76 l-diethylaminodecylpyrazole... 600450 LOGO-1,500 1,2001,500 1.7 '1.7

It will be noted that the number of carbon atoms in the protective inscribe the preparation of members of this series.-

Example I l-DIETHYLAMINOMETHYL-3-NONYLPYRAZOLE A mixture of 6.4 grams (0.033 mole) of 3-nony1- pyrazole, 5 milliliters of 38% aqueous formaldehyde Patented Mar. 15, 19 0 the total numand milliliters of diethylamine in 20 milliliters of ethanol is allowed to stand at room temperature overnight. The alcohol and water (from the formalin), together with excess formaldehyde and diethylamine, is removed under reduced pressure and the residue is distilled at 8.5 mm. pressure. Eight and a half grams of l-diethyl aminomethyl-B-nonylpyrazole is obtained, boiling at 168- 170 C./8.5 mm. (92% yield). This product is redistilled at 2.2 mm. to give three fractions. Fractions 1 and 3, boiling point 154-156 C./2.2 mm., are collected in 1 receiver. The total Weight of the combined fractions is 5.7 grams; n 1.4777. Fraction 2, 1.3 grams, boiling at 156 C.-/2.2 mm., refractive index 1.4776, is analyzed.

Example II 1mtnzrnrnamnoim'rnrnsN-DncYLPrRAzoLn By the procedure described in Example I above, 4 grams of n-decylpyrazole, 6 milliliters of 38% aqueous formaldehyde, and 6 milliliters of diethylamine are dissolved in 50 milliliters of 95% ethanol. After standing overnight at room temperature, the solvents and excess reagents are removed at 20 mm. pressure and the residual oil is distilled at 0.5 mm. Five and nine-tenths grams of the product was recovered, boiling point 155-160 C./0.5 mm. Upon redistillation, boiling point 122- 123 C./0.05 mm., the odor of formaldehyde persists. The distillate is dissolved in 100 milliliters pentane and extracted ten times with 10 milliliter portions of water. The pentane is evaporated and the residue distilled, boiling point 125 127 C./0.0l mm., refractive index 11 1.4728. The yield of 1-diethylaminomethyl-3-11- decylpyrazole is 4.2 grams.

Analyzed for: Theory Found C 73.66 73.57 H 12.02 12.14

Example III 1-DIETHYLAMINOMETHYL-B-UNDECYLPYRAZOLE A mixture of 6.7 grams (0.03 mole) of 3-undecylpyrazole, 6 milliters of 40% aqueous formaldehyde and 6 milliliters of diethylamine in 50 milliliters of ethanol is allowed to stand at C. for 48 hours and then the solution is concentrated under vacuum and the residual oil is distilled to give 8.6 grams of colorless oil which boils at l28130 C./0.2 mm. This is dissolved in 200 milliliters of pentane and the solution is washed with eight 25 ml.-portions of water. The pentane solution is evaporated and the oil is again distilled at 0.2 mm. to yield 7.6 grams (83%) of 1-diethylaminomethyl-3-undecylpyrazole which boils at 128-130 C. and has a refractive index n 1.4780.

Example IV rmnTHYLAMINoMnTHYm-n-nODECYLPYRAZOLE tive index 11 1.4778.

Analyzed for: Theory Found C 74.70 74.70 H 12.23 12.32 N 13.07 12.93

The percentage of the Mannich base in therapeutic compositions may be varied. It is necessary that the active ingredient constitute a portion such that suitable dosage will be obtained. The percentage of active agent may be conveniently 10% or 25% or even 50% since activity increases with the concentration of active material. Tablets containing from about 25 to about 50 milligrams of the active Mannich base are particularly useful. 7

The following formulations are intended to be illustrative only, and may be varied or modified to a considerable extent without departing from the spirit of the invention. It is, therefore, not intended to limit the invention to the specific embodiments herein set forth.

Example V I G. Calcium carbonate 0.500 1-diethylaminomethyl-3-undecylpyrazole 0.050 Calcium stearate 0.050

The 1-diethylaminomethyl-3-undecylpyrazole is adsorbed onto 10% of the calcium carbonate by mixing. The remaining calcium carbonate, previously granulated with water and dried, is added to this pyrazole mixture. The calcium stearate is then added and after mixing until uniform, the mixture is compressed into tablets.

The l-diethylamino'methyl-3-undecylpyrazole is adsorbed onto 10% of the aluminum hydroxide with mixing. The remainder of the aluminum hydroxide is then granulated with the sucrose, lactose, and gelatin solution and dried at 50 C. These granules are then mixed with the pyrazole-aluminum hydroxide composition and magnesium stearate until uniform and compressed into tablets.

It will be apparent to those skilled in the art that numerous variations, modifications, and extensions of the principles involved may be made without departing from the spirit and scope of the invention. All such variations, modifications and extensions are to be understood as included within the ambit of the appended claims.

What is claimed is:

1. A compound having the formula References Cited in the file of this patent Huttel et al.: Chem.'Ber., vol. 85, pp. 820-6 (1952). Buchi et al.: Chem. Abstracts, vol. 49, col. 10936 (1955). 

1. A COMPOUND HAVING THE FORMULA 